Acute lung injury (ALI) affects more than 200,000 patients in the U.S. each year and is an important cause of morbidity and mortality in hospitalized patients. Our work has shown that Fas-dependent pathways are active in the lungs of patients with ALI, and that stimulation of Fas-dependent pathways causes epithelial apoptosis and inflammation in the lungs of rabbits and mice. Published data and our preliminary studies show that chronic stimulation of Fas-dependent pathways leads to lung fibrosis. The major goal of this proposal is to determine the mechanisms linking activation of the Fas/FasL system in the lungs with the development of lung injury. The main hypothesis is that the Fas/FasL system plays an essential role in the pathogenesis of acute lung injury in mice, by a mechanism involving both apoptosis of alveolar epithelial cells, and activation of an apoptosis-independent transcriptional response in the alveolar epithelium. This hypothesis will be tested with the following specific aims: Aim 1: Determine the importance of apoptosis of alveolar epithelial cells in the development of acute lung injury in vivo. Aim 2: Determine how inhibition of apoptosis alters the transcriptional response to Fas activation in primary alveolar epithelial cells. Aim 3: Determine the factors that modulate the bioactivity of soluble Fas ligand in the lungs. Experimental approach: Murine models of lung injury and culture of lung epithelial cells will be used to address the specific aims, taking advantage of transgenic mice with specific gene deficiencies. Importance of the Results. The results of these studies will fill important gaps in our understanding of the link between epithelial apoptosis and fibrosis in the lungs of patients with acute lung injury, and could lead to novel new treatments to reduce pulmonary dysfunction and improve outcome for critically ill patients. Relevance for public Health: This study will help us understand the mechanisms that result in respiratory failure in patients who are critically ill. In addition, we will investigate the potential treatments that will facilitate the repair of injured lungs.